Use of inhibitors of the activity of retinoic acid for treating sensit ive skin and/or acute damage induced by UV radiation

ABSTRACT

The invention concerns tye use of a inhibitor of retinoic acid as sole ingredient in a pharmaceutical or cosmetic composition comprising administering effective amount of the composition to treat sensitive skin or skin damage induced by UV radiation.

This application of 371 of PCT/FR97/01879 filed on Oct. 20, 1997.

The present invention relates to a use of at least one inhibitor of theactivity of retinoid acid in a cosmetic composition or for themanufacture of a pharmaceutical composition, the inhibitor of theactivity of retinoid acid or the pharmaceutical composition beingintended for treating sensitive skins and/or the acute damage induced byUV radiation.

It is known that some skins are more sensitive than others.

The symptoms of sensitive skins have until now been poorly characterizedand the problem of these skins have been poorly defined because of this;no-one knew exactly the process implicated in the sensitivity of theskin. Some thought that a sensitive skin was a skin which reacted tocosmetic products, others that it was a skin which reacted to severalexternal factors, not necessarily linked to cosmetic products.

Some tests have been evaluated in order to try to understand sensitiveskins, for example tests based on lactic acid and DMSO which are knownto be irritant substances: see for example the article by K.Lammintausta et al., Dermatoses, 1988, 36, pages 45-49; and the articleby T. Agner and J. Serup, Clinical and Experimental Dermatology, 1989,14, pages 214-217. However, these tests do not make it possible tocharacterize sensitive skins.

Moreover, sensitive skins have been assimilated with allergic skins.

Because the characteristics of sensitive skins were poorly known, it hasup until now been very difficult to treat them, and they have beentreated indirectly, for example by limiting, in cosmetic ordermatological compositions, the use of products with an irritantcharacter such as surfactants, preservatives, solvents, propellants orperfumes.

Numerous clinical tests have since been performed and the symptomslinked to sensitive skins have thus been determined. These symptoms arein particular subjective signs, which are essentially dysaestheticsensations. Dysaesthetic sensations are understood to mean sensationswhich are painful to a greater or lesser degree and which are felt in acutaneous zone such as pricking, formication, itching or pruritus,inflammation, discomfort, twitching and the like.

It has been possible to show, in addition, that a sensitive skin was notan allergic skin. Indeed, an allergic skin is a skin which reacts to anexternal agent, an allergen, which triggers an allergic reaction. It isan immunological process which occurs only when an allergen is presentand which affects only sensitized subjects. The essential characteristicof the sensitive skin is, according to the applicant, on the contrary, amechanism of response to external factors, which can affect anyindividual, even though the individuals said to have sensitive skinreact thereto more quickly than others. This mechanism is notimmunological, it is aspecific.

Sensitive skins can be divided into two large clinical forms, theirritable and/or reactive skins and the intolerant skins.

An irritable and/or reactive skin is a skin which reacts through apruritus, that is to say through itching, or through pricking, tovarious factors such as the environment (exposure to excessive UV rays),emotions, food, wind, rubbing, razors, soap, surfactants, hard waterwith a high chalk concentration, temperature variations or wool.

An intolerant skin is a skin which reacts to sensations of inflammation,twitching, formication and/or reddening, to various factors such as theenvironment (exposure to excessive UV rays), emotion and food.

Excessive exposure of the skin to UV rays can lead to acute cutaneousdamage, such as an erythematous and/or irritated and/or red and/orswollen and/or oedematous and/or desquamatory skin. This acute cutaneousdamage leads to what is commonly called “sunburn”. This acute damage isto be distinguished from chronic damage, such as cancerous pathologiesor a photoaged skin, which corresponds mainly to dermal damage, andsubsidiarily to epidermal damage. “Sensitive” scalps have a moreunivocal clinical semiology: the sensations of pruritus and/or prickingand/or inflammation are essentially triggered by local factors such asrubbing, soap, surfactants, hard water with a high chalk concentration,shampoos or lotions. These sensations are also sometimes triggered byfactors such as the environment, emotion and/or food.

Moreover, in some anatomical regions such as the large folds (inguinal,genital, axillary, popliteal, anal, submammary or elbow bend regions)and the feet, sensitive skin is manifested by pruriginous sensationsand/or dysaesthetic sensations (inflammation, pricking) linked inparticular to sweating, rubbing, wool, surfactants, hard water with ahigh chalk concentration and/or variations in temperature.

The products having an irritant character can be used in cosmetic orpharmaceutical compositions, and more particularly dermatologicalcompositions, quite obviously for other effects. Thus, they aregenerally used as active agents, surfactants, preservatives, perfumes,solvents or propellants for the said compositions.

However, because of this undesirable effect, these products aregenerally used in very low doses. The use of these products in a smallquantity may then prove to be of little advantage compared with the useof other less active but less irritant or not irritant products whichare therefore used in a larger quantity.

Consequently, there is a need in the cosmetic and pharmaceutical fieldto find a means which makes it possible to use these products, withoutthe latter exhibiting an irritant character which can be criticized bythe user.

It is known, in general, that all-trans- retinoic acid acts on thedifferentiation and/or the proliferation of cells by interacting withnuclear receptors or RARs (retinoic acid receptors) contained in thecell nucleus. Numerous synthetic structural analogues ofall-trans-retinoic acid or of 9-cis-retinoic acid, commonly called“retinoids”, have been described so far in the literature. There are sofar three identified sub-types of RAR receptors called α-RAR, β-RAR andγ-RAR, respectively. These receptors, after binding of the ligand (i.e.of all-trans-retinoic acid), interact with the promoter region of genesregulated by retinoic acid at the level of specific response elements(RARE).

Some analogues can bind and activate a particular RAR (α, β or γ)receptor sub-type. Finally, other analogues exhibit no particularselective activity towards these various receptors. To this end, and forexample, all-trans-retinoic acid activates the RARs (RAR specificagonist ligand), all sub-types taken into consideration.

Retinoic acid and retinoids in general have been claimed for treatingthe following disorders or conditions: acne vulgaris, comedo-type acne,polymorphic acne, acne rosacea, nodulocystic acne, acne conglobata,senile acne, secondary acne such as solar acne, acne medicamentosa oroccupational acne; other keratinization types of disorders, inparticular ichthyosis, ichthyosiform states, Darrier's disease,keratosis palmaris et plantaris, leucoplakia and leucoplakia-likestates, skin or mucosal (buccal) lichen; other dermatological conditionslinked to a keratinization disorder with an inflammatory and/orimmunoallergic component and in particular all forms of psoriasiswhether cutaneous, mucosal or ungual, and even psoriatic rheumatism, oralternatively skin atopy, such as eczema or respiratory atopy oralternatively gingival hypertrophy; damage induced by UV radiation; skinageing, whether photoinduced or chronologic or actinic keratoses andpigmentations or any pathology associated with chronologic or actinicageing; healing disorders or vibices; disorders of sebaceous functionsuch as hyperseborrhoea of acne or simple seborrhoea.

The combination of compounds which are agonists of the α-RARs and γ-RARswith α-RAR antagonists for treating photoaged skins has also beendescribed in patent application WO 96/30009, specifying that the α-RARantagonists alone are not active for this type of treatment.

Retinoic acid and retinoids in general, by binding with the RARreceptors, make it possible to regulate the activity of the RARreceptors and to treat the above disorders or conditions.

As regards cutaneous atopies, it is known that they exhibit animmunological component.

Thus, it could therefore be thought that inhibitors of the activity ofretinoic acid did not exhibit any activity on sensitive skin, as definedabove, and on the damage induced by UV radiation.

It is known that retinoic acid and its analogues (also called retinoids)are capable of inducing the differentiation of mouse embryonicteratocarcinoma cells (F9). The secretion of plasminogen activator whichaccompanies this differentiation is an indication of the biologicalresponse of the F9 cells to the retinoids. It is also known that thecapacity of these retinoids to induce plasminogen activator is directlycorrelated with the affinity which they have on the RAR receptors whichare endogenous to the F9 cells (Skin pharmacol. 1990, 3, pp. 256-267).

The antagonists of retinoic acid inhibit the activity of retinoic acidor its metabolites at the cellular level. These are more particularlythe RAR antagonists which bind to the RAR receptors, but do not inducethe activity observed for retinoic acid or the retinoids, such as thatobserved on the F9 cells.

Thus, it has been shown that antagonists of the α-RAR receptors inhibitthe cellular differentiation induced by the retinoids on cells of theHL60 cell line or, on the contrary, reverse the inhibition of theproliferation of mouse B cells which is induced by the retinoids (C.Apfel & al., Proc. Natl. Acad. Sci. USA, 89, 1992, 7129-7133).

One of the aims of the present invention is therefore to providecompounds which can treat sensitive skins.

Another aim is to provide compounds which can in particular make itpossible to use products in cosmetic or pharmaceutical compositions,more particularly dermatological compositions, without these productsexhibiting an irritant character which can be criticized by the user.

Another aim is to provide a treatment of the acute cutaneous damage dueto exposure to UV radiation.

These aims and others are achieved by the present invention whichrelates to the use of at least one inhibitor of the activity of retinoicacid in a cosmetic composition or for the preparation of apharmaceutical composition, the inhibitor of the activity of retinoicacid or the pharmaceutical composition being intended for treatingsensitive skins and/or the acute cutaneous damage induced by UVradiation.

The pharmaceutical composition is preferably a dermatologicalcomposition.

Sensitive skins and/or the acute cutaneous damage induced by UVradiation are as defined above.

Within the framework of the present invention, the treatment can becarried out in a preventive or curative manner. In the case of acutecutaneous damage induced by UV radiation, it is preferably carried outin a curative manner.

The present invention also relates to the use of at least one inhibitorof the activity of retinoic acid in a cosmetic composition or for thepreparation of a pharmaceutical composition, the inhibitor of theactivity of retinoic acid or the pharmaceutical composition beingintended for treating cutaneous irritation and/or erythema and/orreddening and/or dysaesthetic sensations and/or sensations ofinflammation and/or pruritus and/or pricking and/or formication and/oritching and/or twitching of the skin.

More particularly, the inhibitor of the activity of retinoic acid or thepharmaceutical composition is intended for treating erythema and/orirritation and/or reddening and/or swelling and/or oedema and/ordesquamation due to UV radiation.

The inhibitors of the activity of retinoic acid can act according to twopathways, the first by accelerating the cellular metabolism of retinoicacid so as to reduce the cellular concentration of the latter, thesecond by antagonizing its action at the cellular level.

The inhibitors of the activity of retinoic acid can therefore be,according to the invention, accelerators of the metabolism of retinoicacid or antagonists, reverse agonists or partial agonists of retinoicacid.

By antagonists of retinoic acid, there is preferably understoodaccording to the invention the compounds which inhibit the action ofretinoic acid and/or of its metabolites and/or of the retinoids. Theyare more particularly RAR antagonists which bind to the RAR receptorswithout, however, activating them. Thus, they do not induce thedifferentiation of these F9 cells, but bind nevertheless to the RARs,this binding being of the antagonist type. The F9 test is that describedin the article of Skin pharmacol. 1990, 3, pp. 256-267.

The ability of a compound to bind to the RARs is determined by means oftests which are conventional for persons skilled in the art. These testsare in particular described in the following references: (1) “SelectiveSynthetic Ligands for Nuclear Retinoic Acid Receptor Subtypes” inRETINOIDS, Progress in Research and Clinical Applications, Chapter 19(pp 261-267), Marcel Dekker Inc, edited by Maria A. Livrea and LesterPacker; (2) “Synthetic Retinoids: Receptor Selectivity and BiologicalActivity” in Pharmacol Skin, Basel, Karger, 1993, Volume 5, pp 117-127;(3) “Selective Synthetic Ligands for Human Nuclear Retinoic AcidReceptors” in Skin Pharmacology, 1992, Vol. 5, pp 57-65; (4)“Identification of Synthetic Retinoids with Selectivity for HumanNuclear Retinoic Acid Receptor-γ” in Biochemical and BiophysicalResearch Communications, Vol. 186, No. 2, July 1992, pp 977-983; (5)“Selective High Affinity RAR-α or RAR-β Retinoic Acid Receptor Ligands”in Mol. Pharmacol., Vol. 40, pp 556-562.

The antagonists of retinoic acid are in particular the compoundsdescribed in patent applications EP 661 259, EP 658 553, EP 568 898, WO95/33745 and WO 94/14777, and in several scientific publications, inparticular EYROLLES & al (J. Med. Chem., 37, 1994, 1508-1517; Med. Chem.Res., 2, 1992, 361-367) and KANEKO & al (Med. Chem. Res., 1, 1991,220-225) incorporated herein by reference and which inhibit the actionof retinoic acid and/or of the retinoids.

The RAR antagonists of use according to the invention are in particularselected from the following compounds:

4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid,

4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]salicylic acid,

4-{f[5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]ethynyl}benzoicacid,

(E)-4-[2-(4,4-dimethyl-7-heptyloxy-1,1-dioxo-3,4-dihydro-2H-1-benzothiopyran-6-yl)propenyl]benzoicacid,

4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoicacid,

4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)thioanthra[1,2-b]pyrrol-3-yl]benzoicacid,

4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-d]pyrazol-3-yl]benzoicacid,

4-[3-(diamantyl)-4-methoxybenzamido]benzoic acid,

4-[3-(diamantyl)-4-methoxybenzoyloxy]benzoic acid,

4-(N-phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtho[2,3-d]imidazol-2-yl)benzoicacid,

4-(N-benzyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtho[2,3-d]imidazol-2-yl)benzoicacid,

4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10-pentamethylbenzo[c]-naphtho[2,3-b][1,4]diazepin-3-yl)benzoicacid,

4-[l-(1-methoxy-2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-anthracenyl]benzoicacid,

7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid,

6-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]nicotinic acid,

4-(5,5-dimethyl-8-phenyl-5,6-dihydronaphthalen-2-ylethynyl)benzoic acid,

4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoicacid.

Preferably,4-[7-(1-adamantyl)-6-methoxyethoxy-methoxy-2-naphthyl]benzoic acid,4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]salicylic acid,7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid or 6-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]nicotinicacid is used.

The cosmetic or pharmaceutical composition comprising at least oneinhibitor of the activity of retinoic acid comprises a cosmetically orpharmaceutically acceptable carrier compatible with the mode ofadministration selected.

The quantity of inhibitor of the activity of retinoic acid is aneffective quantity depending of course on the desired treatment and thenature of the chosen compound; it is therefore determined by personsskilled in the art.

The administration of the compounds according to the invention may becarried out by the systemic (especially enteral or parenteral), topicalor ocular route.

By the enteral route, the composition is more particularly apharmaceutical composition which may be provided in the form of tablets,gelatine capsules, sugar-coated tablets, syrups, suspensions, solutions,powders, granules, emulsions, lipid or polymeric microspheres ornanospheres or vesicles which allow a controlled release. By theparenteral route, the composition, more particularly the pharmaceuticalcomposition, may be provided in the form of solutions, emulsions orsuspensions for infusion or for injection.

The inhibitors of the activity of retinoic acid, more particularly theantagonists of retinoic acid are generally administered by the systemicroute in a daily dose of about 0.01 mg/kg to 100 mg/kg of body weight,and this at the rate of 1 to 3 doses.

By the topical route, the composition is a cosmetic or pharmaceuticalcomposition, more particularly intended for the treatment of the skin.It can therefore be provided in the form of solutions or suspensions,ointments, pommades, creams, milks, gels, powders, impregnated pads,lotions, sprays, or foaming or cleansing products. It can also beprovided in the form of lipid or polymeric microspheres or nanospheresor vesicles or of polymeric patches, hydrogels or dressings allowing acontrolled release. This composition for the topical route can,moreover, be provided either in anhydrous form or in an aqueous form.

It can also be used on hair, to treat the scalp, in the form of aqueous,alcoholic or aqueous- alcoholic solutions, in the form of creams, gels,emulsions, foams or alternatively in the form of aerosol compositionsalso containing a pressurized propelling agent.

These compositions constitute in particular cleansing, protective,treatment or care creams for the face, the hands, the feet, the largeanatomical folds or the body (for example day creams, night creams,make-up removing creams, foundation creams, anti-sun creams), fluidfoundations, make-up removing milks, protective or care body milks,anti-sun milks, lotions, gels or foams for skin care, such as cleansinglotions, anti-sun lotions, artificial tanning lotions, bathcompositions, deodorant compositions containing a bactericidal agent,aftershave gels or lotions, depilatory creams, compositions againstinsect bites, anti-pain compositions.

The compositions according to the invention may also consists of solidpreparations constituting cleansing cakes or soaps.

The compositions may also be packaged in the form of an aerosolcomposition also containing a pressurized propelling agent.

The inhibitor of the activity of retinoic acid may also be incorporatedinto various compositions for hair care, and particularly shampoos, hairsetting lotions, treatment lotions, hair-styling creams or gels, dyecompositions (particularly oxidation dyes) optionally in the form ofdyeing shampoos, restructuring lotions for the hair, permanent wavingcompositions (particularly compositions for the first stage of apermanent waving), anti-hair loss lotions or gels and the like.

By the ocular route, the composition may in this case be provided in theform of ointments, creams, gels or collyria which are appropriate forthis specific application.

This composition for topical or ocular use contains at least oneantagonist of retinoic acid at a concentration preferably ranging from0.000001% to 5% by weight relative to the total weight of thecomposition, more particularly ranging from 0.0001% to 0.1% by weight.

The composition according to the invention may, in addition, containinert or even pharmacodynamically or cosmetically active additives orcombinations of these additives, and in particular wetting agents;emollients; moisturizing agents such as glycerol, PEG 400,thiamorpholinone and its derivatives or alternatively urea; carotenoidsand, in particular, β-carotene.

The composition may also contain taste-enhancing agents, preservativessuch as esters of parahydroxybenzoic acid, stabilizing agents,humidity-regulating agents, pH-regulating agents, osmoticpressure-modifying agents, emulsifying agents, photoprotective agentssuch as UV-A and/or UV-B screening agents, hydrophilic or lipophilicanti-oxidants, such as α-tocopherol, butylated hydroxyanisole orbutylated hydroxytoluene, chelators such as EDTA and its salts.

The inhibitor of the activity of retinoic acid and the other activecompounds can be administered together in the same cosmetic orpharmaceutical composition, or alternatively separately in separatecompositions, simultaneously or spaced out over time.

The quantities of the various constituents of the compositions accordingto the invention are those conventionally used in the fields considered.

Of course the nature and the quantity of these constituents are chosenso as not to interfere with the activity of the inhibitor of theactivity of retinoic acid for treating sensitive skins and/or the acutecutaneous damage induced by UV radiation.

The inhibitors of the activity of retinoic acid can be combined, interalia, with active agents intended in particular for the preventionand/or treatment of skin conditions.

Among these active agents, there may be mentioned, by way of example:

agents modulating skin differentiation and/or proliferation and/orpigmentation such as vitamin D and its derivatives, oestrogens such asestradiol, kojic acid or hydroquinone;

antibacterials such as clindamycin phosphate, erythromycin orantibiotics of the tetracycline class;

antiparasitic agents, in particular metronidazole, crotamiton orpyrethrinoids;

antifungal agents, in particular the compounds belonging to theimidazole class such as econazole, ketoconazole or miconazole or theirsalts, the polyene compounds, such as amphotericin B, the compounds ofthe allylamine family, such as terbinafine, or octopirox;

steroidal anti-inflammatory agents such as hydrocortisone, betamethasonevalerate or clobetasol propionate, or nonsteroidal anti-inflammatoryagents such as ibuprofen and its salts, diclofenac and its salts,acetylsalicylic acid, acetaminophen or glycyrrhetinic acid;

anaesthetic agents such as lidocaine hydrochloride and its derivatives;

antipruriginous agents such as thenaldine, trimeprazine orcyproheptadine;

antiviral agents such as acyclovir;

keratolytic agents such as alpha- and beta- hydroxycarboxylic orbeta-ketocarboxylic acids, their salts, amides or esters and moreparticularly hydroxy acids such as glycolic acid, lactic acid, salicylicacid, citric acid and, in general, fruit acids and 5-n-octanoylsalicylicacid;

anti-free radical agents, such as alpha-tocopherol or its esters,superoxide dismutases, certain metal chelators or ascorbic acid and itsesters;

antiseborrhoeic agents such as progesterone;

antidandruff agents such as octopirox or zinc pyrithione;

anti-acne agents such as benzoyl peroxide.

Advantageously, the inhibitors of the activity of retinoic acid arecombined with active agents with an irritant side effect which arecommonly used in the cosmetic or dermatological field. The presence ofan inhibitor in a cosmetic or dermatological composition containing anactive agent having an irritant effect makes it possible tosubstantially attenuate, or even suppress this effect.

Accordingly, a further subject of the invention is a compositioncontaining a cosmetically or pharmaceutically acceptable medium and atleast one active agent with an irritant side effect, with the exceptionof retinoic acid and retinoids, characterized in that it comprises atleast one inhibitor of the activity of retinoic acid.

In particular, the active agents with an irritant side effect areselected from α-hydroxy acids, β-hydroxy acids, α-keto acids, β-ketoacids, anthralins, anthranoids, peroxides, minoxidil, lithium salts,antimetabolites, vitamin D and its derivatives.

Because of its importance in the sun domain, another subject of thepresent invention is a composition containing a cosmetically orpharmaceutically acceptable medium and at least one photoprotectiveagent, characterized in that it comprises at least one inhibitor of theactivity of retinoic acid.

By way of photoprotective agent, there may be used organic screeningagents which are hydrophlic or lipophilic conventional sun-screeningagents active in the UV-A and/or UV-B region. By way of examples, thesescreening agents may be chosen, alone or as a mixture, from2-phenylbenzimidazole-5-sulphonic acid and its salts, cinnamicderivatives, salicylic derivatives, benzylidenecamphor derivatives,triazine derivatives, benzophenone derivatives, dibenzoylmethanederivatives, β,β-diphenylacrylate derivatives, p-aminobenzoic acidderivatives, menthyl anthranilate, the screening polymers and screeningsilicones described in application WO-93-04665. Other examples oforganic screening agents are given in patent application EP-A 0,487,404.

The organic screening agent(s) are generally present in the compositionsaccording to the invention in an amount ranging from 0.1% to 30%,preferably from 0.5 to 15% by weight relative to the total weight of thecomposition.

A second category of photoprotective agents which are particularlysuitable for the compositions according to the invention is that ofpigments. Preferably, inorganic nanopigments (mean size of the primaryparticles: generally between 5 nm and 100 nm, preferably between 10 and50 nm) of metallic oxides, coated or otherwise, are used such as forexample nanopigments of titanium oxide (amorphous or crystallized in theform of rutile and/or anatase), of iron, of zinc, of zirconium or ofcerium which are all photoprotective agents well known per se which actby physically blocking (reflection and/or diffusion) the UV radiation.Conventional coating agents are moreover alumina and/or aluminiumstearate or alternatively silicones. Such nanopigments of metallicoxides, coated or non-coated, are in particular described in patentapplications EP-A-0,518,772 and EP-A-0,518,773.

The inorganic (nano)pigment(s) may be present in the compositionsaccording to the invention in an amount of between 0.1% and 30%,preferably from 0.5% to 10% by weight relative to the total weight ofthe composition.

The subject of the present invention is, in addition, a process ofcosmetic treatment, characterized in that a composition as describedabove, containing at least one inhibitor of the activity of retinoicacid in a cosmetically acceptable medium is applied to the skin and/orthe hair.

The process of cosmetic treatment of the invention may be carried out inparticular by applying the hygiene or cosmetic compositions as definedabove, according to the usual technique for using these compositions.For example: application of creams, gels, sera, lotions, make-upremoving milks or anti-sun compositions to the skin or to dry hair,application of a hair lotion to wet hair, or shampoos.

Several examples will now be given by way of illustration and with nolimitation being implied.

EXAMPLE 1

Study of the activity of the inhibitors of the activity of retinoic acidfor protecting the skin against the deleterious biological effectsinduced by UV radiation.

The aim of this example is to demonstrate the activity of an RARantagonist in protecting the skin against the acute biological cutaneouseffects induced by UVB radiation.

Method

For these studies, a UVB tube having a peak at 315 nm is.used.

A single irradiation at the dose of 120 mJ/cm² is applied to the ear inBalb/c mice. The irradiation is applied under anaesthetic, the animals,outside the irradiated zone, being protected by a screen.

4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid (RARantagonist) in solution in acetone at the concentrations of 0.01%, 0.03%and 0.1%, or the vehicle alone, is administered by topical applicationto the irradiated ear, in a volume of 20 microliters.

The treatment is administered 30 minutes, 24 hours, 48 hours and 72hours after irradiation.

Every day for 11 days after irradiation (from D1 to D11), clinicalobservations are carried out and the oedema is quantified by measuringthe thickness of the ear with the aid of a micrometer.

Results

In the animals irradiated and not treated, or treated with the vehiclealone, an erythema is observed and an oedema which is clinically visible24 hours after irradiation and reaching a maximum value 9 days afterirradiation. Desquamation appears 4 days after irradiation. Thisphenomenon becomes accentuated during the second week after irradiation.

In the animals treated with4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid, adose-dependent reduction in the erythema, the oedema and thedesquamation is observed. The value of the area under the curve of thethickness of the ear determined by the trapezium method over the D1-D11period is reduced in a statistically significant manner by the treatmentat the doses of 0.03% and 0.1%, by 26% and 55% respectively.

These results clearly show that the inhibitors of the activity ofretinoic acid or of its metabolites and more particularly the RARantagonists, exhibit a reparatory activity on the acute deleteriousbiological effects induced by UVB radiation.

EXAMPLE 2

Study of the evaluation of the inhibitors of retinoic acid forprotecting the skin against the acute deleterious effects induced by UVradiation.

This example is intended to demonstrate the activity of an RARantagonist in protecting the skin against the acute cutaneous biologicaleffects induced by UVB radiation.

Method

Human skin obtained from a healthy donor is transplanted in nude miceaccording to the method described by Demarchez & al (M. Demarchez & al,Develop. Biology, 113, 1986, 90-96; M. Demarchez & al, Develop. Biology,121, 1987, 119-129).

Five months after the transplantation, a single irradiation at the doseof 300 mJ/cm² is applied to half of the transplant with the aid of a UVBlamp having a peak at 315 nanometres. The other half of the transplantprotected by a screen during the irradiation is used as anintra-individual control.

4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-benzoic acid (RARantagonist) in solution in acetone at the concentration of 0.1%, or thevehicle alone, is administered by topical application to the transplanton the day of irradiation and then once per day during the four daysfollowing the irradiation.

24 hours after the last treatment, the mice are subjected to euthanasiaand the skin of the transplants is removed and fixed by freezing for animmunohistochemical study. Various antibodies are used to study theeffect of UVB and of the treatments on the cutaneous morphology:anti-human involucrin (study of epidermal differentiation), AE1(anti-keratin monoclonal antibody), anti-HLADr (Langerhans' cells).

Results UVB radiation induces, in the epidermis of the transplantstreated with the vehicle alone, a slight hyperplasia, a hypergranulosis,a parakeratosis, a disruption of the epidermal differentiation and ofthe “sun burn cells”.

The treatment with4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid limitsthe hypergranulosis and the hyperkeratosis, and reduces the number of“sun burn cells”.

These results clearly show that the inhibitors of the activity ofretinoic acid or of its metabolites, and more particularly the RARantagonists, exhibit a reparatory activity on the acute deleteriousbiological effects induced by UVB radiation.

EXAMPLE 3

Study of the evaluation of the inhibitors of retinoic acid as treatmentfor sensitive skins.

This example is intended to demonstrate the activity of an RARantagonist as regulator of cutaneous homeostasis in the border zones ofa transplant.

Method Human skin obtained from a healthy donor is transplanted in nudemice according to the method described by Demarchez & al (M. Demarchez &al, Develop. Biology, 113, 1986, 90-96; M. Demarchez & al, Develop.Biology, 121, 1987, 119-129). It is well established that in this modelof human skin transplanted in nude mice, the periphery of thetransplants is a zone which is particularly sensitive to chemical agentssuch as irritant products or to physical agents such as UV. Thus, thisperipheral zone may be considered as a model of sensitive skin.

Three months after transplantation,4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid (RARantagonist), in solution in acetone at the concentration of 0.1%, or thevehicle alone, is administered by topical application to the transplantonce per day for six weeks. 24 hours after the last treatment, the miceare subjected to euthanasia and the skin of the transplants is removedand fixed by freezing for an immunohistochemical study. Variousantibodies are used to study the effect of UVB and of the treatments onthe cutaneous morphology: anti-human involucrin (study of epidermaldifferentiation), AE1 (anti-keratin monoclonal antibody).

Results

The transplants treated with the vehicle alone exhibit disruption inepidermal differentiation in the transplant border zone.

4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid doesnot modify the histological appearance of the transplants except at thelevel of the borders of transplants where it regulates epidermaldifferentiation.

These results clearly show that the inhibitors of the activity ofretinoic acid or of its metabolites, and more particularly the RARantagonists, exhibit a modulatory activity on cutaneous homeostasis insensitive skins.

EXAMPLE 4

Study of the evaluation of the inhibitors of retinoic acid as atreatment for sensitive skins.

This example is intended to demonstrate the activity of an RARantagonist as a regulator of cutaneous homeostasis in transplant borderzones.

Method

Human skin obtained from a healthy donor is transplanted in nude miceaccording to the method described by Demarchez & al (M. Demarchez & al,Develop. Biology, 113, 1986, 90-96; M. Demarchez & al, Develop. Biology,121, 1987, 119-129). It is well established that in this model of humanskin transplanted in nude mice, the periphery of the transplants is azone which is particularly sensitive to chemical agents such as irritantproducts or to physical agents such as UV. Thus, this peripheral zonemay be considered as a model of sensitive skin.

Five months after transplantation,4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid (RARantagonist) or4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]salicylic acid insuspension in cremophor EL 25%, or the vehicle alone, is administeredorally once per day for 7 days. 24 hours after the last treatment, themice are subjected to euthanasia and the skin of the transplants isremoved and fixed by freezing for an immunohistochemical study. Variousantibodies are used to study the effect of the treatments on thecutaneous morphology: anti-human involucrin (study of epidermaldifferentiation), AE1 (anti-keratin monoclonal antibody)

Results

The transplants treated with the vehicle alone exhibit disruption ofepidermal differentiation in the transplant border zone.

4-[7-(1-Adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]-benzoic acid and4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]salicylic acid donot modify the histological appearance of the transplants except at thelevel of the borders of transplants where it regulates epidermaldifferentiation.

These results clearly show that the inhibitors of the activity ofretinoic acid or of its metabolites, and more particularly the RARantagonists, exhibit a modulatory activity on cutaneous homeostasis insensitive skins.

EXAMPLE 5

The compositions below are examples of compositions capable of beingused to apply or administer antagonists of retinoic acid with the aim oftreating sensitive skins and/or the acute damage due to UV radiation.

A - ORAL ROUTE (a) Immediate-release 0.2 g tablet (granulation)Antagonist of retinoic acid 0.0010 g Lactose codex 0.1204 gMicrocrystalline cellulose (Avicel PH 101) 0.0640 g Polyvinylpyrrolidone(Kollidon K30) 0.0060 g Colloidal silica (Aerosil 200) 0.0006 gMagnesium stearate 0.0020 g Sodium starch glycolate (Explotab) 0.0060 gPurified water qs granulation (b) Immediate-release 0.8 g tablet (directcompression) Antagonist of retinoic acid 0.0800 g Modified starch(Starch 1500) 0.2984 g Microcrystalline cellulose (Avicel PH 102) 0.4000g Colloidal silica (Aerosil 200) 0.0016 g Magnesium stearate 0.0040 gSodium Croscarmellose (Ac-Di-Sol) 0.0160 g (c) 0.2 g gelatin capsule(soft capsule or hard gelatin capsule filled with liquid) Antagonist ofretinoic acid 0.0050 g Unsaturated polyglycosylated glycerides or 0.1845g vegetable oil (soyabean, maize and the like) White beeswax orhydrogenated castor oil 0.0100 g BHT 0.0001 g dl-α-tocopherol 0.0004 g(d) Oral solution in 5 ml vials Antagonist of retinoic acid 0.0001 gGlycerol 0.7500 g Sorbitol 1.0000 g Propylene glycol 1.0000 gPolyvinylpyrrolidone (Kollidon K25) 0.5000 g Sodium cyclamate 0.0050 gSodium parahydroxybenzoate 0.0040 g Flavouring qs Purified water qs 5 mlB - TOPICAL ROUTE (a) Ointment Antagonist of retinoic acid 0.020 gIsopropyl myristate 81.700 g Fluid petroleum jelly 9.100 g Silica(“Aerosil 200” sold by Degussa) 9.180 g (b) Ointment Antagonist ofretinoic acid 0.300 g Petroleum jelly codex qs 100 g (c) Non-ionicwater-in-oil cream Antagonist of retinoic acid 0.100 g Mixture ofemulsifying lanolin alcohols, 39.900 g of waxes and of oils (“Eucerineanhydre” sold by BDF) Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g (d)Lotion Antagonist of retinoic acid 0.100 g Polyethylene glycol (PEG 400)69.900 g Ethanol 95% 30.000 g (e) Non-ionic oil-in-water creamAntagonist of retinoic acid 1.000 g Cetyl alcohol 4.000 g Glycerolmonostearate 2.500 g PEG 50 stearate 2.500 g Shea butter 9.200 gPropylene glycol 2.000 g Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g

What is clained is:
 1. A method for treating sensitive skin or acutecutaneous damage induced by UV radiation consisting essentially ofapplying an effective amount of a retinoid inhibitor as the sole activeingredient in a pharmaceutical or cosmetic composition.
 2. The method ofclaim 1 characterized in that the refinoid inhibitor is chosen from thefollowing compounds:4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid,4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]salicylic acid,4-{[5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl]ethynyl}benzoicacid,(E)-4-[2-(4,4-dimethyl-7-heptyloxy-1,1-dioxo-3,4-dihydro-2H-1-benzothiopyran-6-yl)propenyl]benzoicacid,4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoicacid,4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)thioanthra[1,2-b]pyrrol-3-yl]benzoicacid,4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-d]pyrazol-3-yl]benzoicacid, 4-[3-(diamantyl)-4-methoxybenzamido]benzoic acid,4-[3-(diamantyl)-4-methoxybenzoyloxy]benzoic acid,4-(N-phenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtho[2,3-d]imidazol-2-yl)benzoicacid,4-(N-benzyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphtho[2,3-d]imidazol-2-yl)benzoicacid,4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10-pentamethylbenzo[c]-naphtho[2,3-b][1,4]diazepin-3-yl)benzoicacid,4-[1-(1-methoxy-2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-anthracenyl]benzoicacid,7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, 6-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]nicotinicacid, 4-(5,5-dimethyl-8-phenyl-5,6-dihydronaphthalen-2-ylethynyl)benzoicacid, and4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoicacid.
 3. The method of claim 2, characterized in that the retinoidinhibitor is chosen from:4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid, 4-[7-(1 -adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]salicylic acid,7-[3-(1-adamantyl)-4-methoxyphenyl]-3,7-dimethyl-2,4,6-heptatrienoicacid, and 6-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]nicotinicacid.
 4. A method for treating a condition selected from the groupconsisting of cutaneous irritation, erythema, reddening, dysaestheticsensations, sensations of inflammation, pruritus, prickling,formication, itching, and twitching of the skin, consisting essentiallyof applying a cosmetic or pharmaceutical composition consistingessentially of an effective amount of at least one inhibitor of retinoicacid.
 5. A method for treating at least one of erythema, irritation,reddening, swelling, edema, and/or desquamation attributable to UVradiation consisting essentially of applying an effective amount of apharmaceutical composition consisting essentially of at least oneinhibitor of retinoic acid.
 6. The method of claim 1, wherein saidpharmaceutical composition is a dermatological composition.
 7. Themethod of claim 1, wherein said composition alleviates sensitive skin oracute cutaneous damage induced by UV radiation.